Time-of-flight (TOF) mass spectrometry involves the acceleration of a pulse of ions from a pulsed ion source, through a flight region where they separate according to their velocity, which is dependent on their mass to charge ratio (m/z), and reach a detector where their times-of-flight are recorded. The times of flight of the ions are then typically converted to their m/z values. Thus, a mass spectrum of the ions can be measured.
Commonly, an ion mirror or other focusing device is used to bring ions with differing energies but the same m/z to an isochronous focal plane, thereby maximising the mass resolution. Various arrangements utilizing multi-reflection to extend the flight path of ions within mass spectrometers are known. Flight path extension is desirable to increase time-of-flight separation of ions within time-of-flight (TOF) mass spectrometers. The ability to distinguish small mass differences between ions (the mass resolving power or resolution) is thereby improved. Improved resolving power, along with advantages in increased mass accuracy and sensitivity that typically accompany it, is an important attribute for a mass spectrometer for a wide range of applications, particularly with regard to applications in biological science, such as proteomics and metabolomics, for example. With flight path extension in certain designs of mass spectrometer however, it can be a problem to maintain a sufficiently high ion transmission.
US2015/0028197 A and US 2015/0028198 A disclose a type of multi-reflection mass spectrometer having an extended flight path wherein two ion mirrors oppose each other in a direction X and both mirrors are generally elongated in a drift direction Y, orthogonal to direction X. Ions injected into the spectrometer are repeatedly reflected back and forth in the X direction between the mirrors, whilst they drift down the Y direction of mirror elongation. Overall, the ion motion follows a zigzag path. The mirrors have a convergence with increasing Y, thereby creating a pseudo-potential gradient along the Y axis that acts as an ion mirror to reverse the ion drift velocity along Y and spatially focus the ions in Y to a focal point where a detector is placed, typically near to the region of ion injection.
In TOF mass spectrometers, ions are typically extracted from an ion source by a pulsed extraction electric field generated by a pulsed high voltage. Examples of such systems are disclosed in U.S. Pat. Nos. 5,569,917 and 7,897,916, which show means of ion extraction from an RF ion trap source. In TOF mass spectrometry, pulsed ion extraction involving pulsed high voltages from an ion source using MALDI and/or orthogonal acceleration are also common.
A problem arising with such methods is that the rise time of the pulsed extraction voltage has been found to induce a mass dependent perturbation to the kinetic energy of the extracted ions, as ions of different m/z separate spatially within the source, traversing a varying portion of the extraction field before the field reaches its maximum strength. Thus, relatively lighter ions can exit the ion source with a substantially lower energy than relatively higher m/z ions if the rise time is too long. High extraction fields, which are desirable to minimise the ion turnaround time within the ion source and to improve mass resolution, exacerbate the problem.
This problem is usually limited to low mass ions (e.g. m/z <200) and in conventional time-of-flight instruments incorporating an ion mirror it does not present a severe problem as they are normally tolerant to energy deviations of >200 eV. However, the inventors have found that in certain complex time-of-flight analyzer designs, such as that shown in US 2015/0028198 A1 for example, that incorporate a long, highly folded ion flight path, the transmission of the ions to a final detector can be dependent on the ions having a narrow ion energy range, e.g. less than 200 eV.
One strategy to solve the problem is to limit the appearance of the energy perturbation in the first place. This can be done, for example, by reducing the rise time of the ion source extraction pulse. However, this becomes increasingly difficult beyond a certain point. An alternative strategy is to reduce the extraction pulse amplitude but this will increase ion turnaround time and typically reduce the resolution of the instrument. Yet another option is to increase the flight energy of the ions in the analyzer and in this regard up to 20 kV is already commonly used. However, this diminishes the overall time-of-flight and therefore the instrument resolution. Moreover, very high applied voltages introduce cost, bulk and design complexity to an instrument.
In WO 2010/007373 A is disclosed a stigmatic imaging TOF mass spectrometer in which a potential gradient is applied to a spatial focusing lens correlated with ion arrival time for a limited range of masses to achieve good image focusing over the limited mass range. However, energy correction is not described.
In US 2013/0068944 A is described an approach to problems associated with injection of pulses of ions, e.g. from a MALDI source, into an ion trap mass analyzer such as an RF trap, FT-ICR trap or an electrostatic orbital trap such as an Orbitrap™ mass analyzer. There the problems are essentially related to the limitation on the mass range of ions that can be received from the pulsed source by the ion trap mass analyzer and trapped therein and the mass dependent spread of energies is relatively low, being typically only 5 eV/kDa, compared to the spread of energies typically associated with pulsed ion sources for TOF mass spectrometers. A series of cylindrical electrodes are provided downstream of the pulsed ion source on the axis along which the ions travel to which a time dependent potential is applied to change ion energies. For certain types of ion trap mass analyzer, the heavier ions are reduced in energy by the time dependent potential to improve trapping in the ion trap. In other embodiments, for example for injection into an orbital trap, the heavier ions arriving later are increased in energy in order to increase the mass range of ions that are trapped in the analyzer.
It is an aim of the invention to address the unequal average energy of ions of different masses when injected into a time-of-flight mass analyzer, which can result in reduced ion transmission and/or instrument resolving power, in particular for low mass ions, thus limiting instrument mass range.